Traditional wound closure methods, such as staples and sutures, have numerous drawbacks, including the possible occurrence of inflammation, irritation, infection, wound gap, and leakage. The cosmetic results of the use of staples and sutures can also be undesirable. In corneal applications, sutures often produce astigmatism due to uneven suture tension. In tissue grafting techniques, sutures can lead to a variety of complications in wound healing, including foreign body responses that cause scarring. Repair of injuries to tendons and ligaments involve an additional component whereby the wound must return to functional integrity, which would be severely compromised by the presence of scar tissue or the failure of sutures. Traditional wound closure and/or tissue adhesion methods suffer from a number of drawbacks that are addressed by the present invention.
Possible alternatives to sutures include hemostatic adhesives, such as fibrin sealants (Henrick et al. (1987) J Cataract Refract Surg 13:551-553; Henrick et al. (1991) J Cataract Refract Surg 17:551-555), cyanoacrylate adhesives (Shigemitsu et al. (1997) International Ophthalmology 20:323-328), and photodynamic tissue glue, composed of a mixture of riboflavin-5-phosphate and fibrinogen, which has been reported to close cataract incisions and attach donor cornea in corneal transplants (Goins et al. (1997) J Cataract Refract Surg 23:1331-1338; Goins et al. (1998) J Cataract Refract Surg 24:1566-1570; U.S. Pat. No. 5,552,452). In addition, temperature-controlled tissue welding has been attempted in bovine cornea and rat intestine (Barak et al. (1997) Surv Ophthalmol 42 Supp.1:S77-81; Cilesiz et al. (1997) Lasers Surg Med 21:269-86). Photochemical tissue welding of dura mater has also been reported, using 1,8 naphthalimides irradiated with visible light (Judy et al. (1993) Proc. SPIE—Int. Soc. Opt. Eng. 1876:175-179).
Tissue grafts and/or tissue substitutes (e.g., extracellular matrix-based scaffolds, such as collagen and proteoglycan, and/or other engineered tissue implants) are important components used in structural tissue engineering. Although many tissue grafts and/or substitutes are made of naturally occurring biomaterials, these structures, once implanted, do not attach well to the target tissue and can lack the ability to hold sutures. As a result, additional support material, such as silicon tubing, is implanted for further support and integration of the implant with the target tissue. The disadvantage of this method is that a second surgical procedure is often required for the removal of the support material once the implants become integrated with the host tissue.
In particular, tissue grafts comprising skin grafts and/or skin substitutes are widely used in surgical procedures such as skin transplantation, burn and ulcer wound management and plastic surgery. Current fixation aids for grafting mainly consist of mechanical and adhesive means (Bass & Treat (1995) Lasers Surg Med 17: 315-49). Surgical sutures and staples mechanically hold the tissue in position while tissue and fibrin glues chemically/biochemically bond the graft to the host. However, the use of sutures and staples has low aesthetic/cosmetic value and may lead to foreign-body reactions as well as wound complications (Bass & Treat (1995) Lasers Surg Med 17: 315-49). The use of tissue glues such as cyanoacrylate provides excellent binding strength but results in persistent inflammation and foreign body giant cell reaction (Forseth et al. (1992) J Long Term Eff Med Implants 2(4): 221-33, Toriumi et al. (1990) Arch Otololaryngol Head Neck Surg 116: 546-550). Although the use of autogenous fibrin glue eliminates the foreign-body reactions and the associated complications, it elicits other problems. Firstly, it is costly and time-consuming to extract and purify autogenous fibrinogen from the patient's blood (Dahlstrom et al. (1991) Skin Transplantation 89(5): 968-72) and secondly, the mechanical outcome is not satisfactory since the breaking strength at the interface was less than 0.2N/cm2 (Dahlstrom et al. (1991) Skin Transplantation 89(5): 968-72).
Tendon and ligament injuries, including Achilles tendon rupture (Davis et al. (1999) Mil Med 164(12): 872-3; Maffulli et al. (1999) Clin J Sport Med 9(3): 157-60; Houshian et al. (1998) Injury 29(9): 651-4), are extremely common, and can occur in various anatomical regions (Best & Garrett Jr (1993) Orthopaedic Sports Medicine pp. 1-45): rupture or inflammation may occur at the supraspinatus and subscapularis tendon of the shoulder region, and in the biceps and triceps tendons of the upper limb; extensive tendon and ligament injuries can occur in both hands and fingers, disturbing the normal function of the appendage and making delicate movements impossible; knee injuries often involve the medial collateral ligament (MCL), anterior cruciate ligament (ACL) or posterior cruciate ligament (PCL), and can also involve the patellar tendon. Tendons are usually injured upon excessive acceleration or deceleration, especially when the associated muscles become fatigued. The injury often occurs as a laceration or an avulsion from the bone and tendon transaction, which is deemed rupture of the tendon. Such injuries are very common in individuals who frequently engage in strenuous activities for extended periods of time.
Although many nonsurgical treatment regimens such as bracing, rehabilitation program, immobilization, passive controlled movement and ultrasound have been used, surgical repair and reconstruction of a completely torn tendon or ligament is still the preferred treatment, in particular among young patients and those who require an early return to normal activities (Leppilahti & Orava (1998) Sports Med 25(2): 79-100), such as athletes and military personnel. Typical treatments include surgical repair using the Kessler suture procedure and the pedicle flap turn-down procedure (Shereff (1993) Atlas of foot and ankle surgery pp. 304-11) in achilles tendon, surgical reconstruction of torn anterior cruciate ligament (ACL) using autogenous patellar tendon graft (Shino et al. (1993) Am J Sports Med 21(4): 609-616) and reconstruction of ruptured posterior cruciate ligament (PCL) (Bosch et al. (1994) Acta Orthop Belg 60(suppl): 57-61).
Despite its popularity, the current surgical management of musculoskeletal tissues is not problem-free. The major complaint involving surgical treatment is the high rate of complications (Leppilahti & Orava (1998) Sports Med 25(2): 79-100). Most of these procedures involve multiple sutures and staples, which may be associated with wound complications such as infection and necrosis (Shereff (1993) Atlas of foot and ankle surgery pp. 304-11; Koh & Lim (1999) Hand Surg 4(2): 197-202). For procedures making use of autogenous tendon or facia grafts for reinforcement or reconstruction, additional soft tissue injuries at the donor sites are created which make the procedure more invasive and may lead to donor site morbidity. Recurrent rupture, skin adhesions and excessive scarring are other surgery-associated problems.
These complications have prompted investigation into laser tissue welding as an alternative or supplement to surgical options. Laser tissue welding is a developing technique with numerous clinical applications for many surgical specialties including orthopedics (Bass & Treat (1995) Lasers Surg Med 17: 315-49), of which repair of tendons is a potential use. An immediate regaining of partial strength after repair is essential because of the large stress the tendon is subjected to post-operatively. A previous report (Kilkelly & Choma (1996) Laser Surg Med 19: 487-91) using CO2 and Argon lasers, showed that thermal welding of ruptured achilles tendon in rats led to ˜50-70% tensile strength recovery at 2 weeks post-op but no immediate tensile strength improvement. Other modes of laser tissue interaction mechanisms such as low energy laser photostimulation have also been studied to improve tendon repair by stimulating the intrinsic tendon healing. These means were found to induce a significant (˜30%) increase in collagen production but insignificant increase (˜10%) in mature crosslinks in ruptured rabbit achilles tendon (Reddy et al. (1998) Laser Surg Med 22: 281-7). In addition, the mechanical properties of the repaired tendon, in particular stress and stiffness demonstrated a ˜30% but statistically insignificant increase (Reddy et al. (1998) Med Sci Sports Exerc 30(6): 794-800).
The ideal technique for tissue adhesion would be simpler, more rapid, and prone to fewer post-operative complications than conventional techniques. In the cornea, an ideal tissue repair or wound closure technique would produce a watertight seal without inducing astigmatism. In tissue grafts and/or tissue substitutes, such as collagen-based scaffolds, the ideal technique would enhance fixation to the surrounding host tissues. In particular, skin grafting techniques enabling rapid and sustained adherence to the wound surface and the ability to resist shear stress are ideal for successful graft take. Repair of injuries to tendons and ligaments would ideally minimize or eliminate the use of multiple sutures and autogenous tendon grafts, minimize complications associated with foreign-body reactions, and minimize the thermal damage to surrounding tissue currently associated with thermal laser tissue welding.
Initial repair technique plays an important role in determining overall outcome in peripheral nerve regeneration after injury (de Medinaceli et al. (1982), Exp Neurol 77(3): 634-43). Microsurgical re-approximation of severed nerve ends is currently the most commonly used technique for repair of peripheral nerve injuries in which a significant deficit of neural tissue does not occur. Unfortunately, even in more favorable lesions, such as median or ulnar nerve injuries in the forearm, only 10% of patients who undergo microsurgical repair achieve an excellent recovery, i.e. full muscle strength and normal two-point discrimination. There are both biologic and technical reasons for this. Following peripheral nerve injury, a large proportion of the lower motor neurons and sensory neurons from the injured nerve undergo apoptotic death, with loss of up to 30% of the neurons within the nerve. This biologic limitation virtually ensures inadequate or absent recovery distally for any proximal nerve injury. Although current microsurgical techniques utilizing end-to-end repair and nerve grafting are adequate for more distal injuries, those with longer nerve gaps and injuries that are more proximal rarely achieve complete recovery. Further complicating this issue, surgery itself is traumatic to the nervous tissue with suture material acting as a potential nidus for the formation of scar tissue, which inhibits regeneration of proximal nerve fibers (Korff et al (1992), Otolaryngol-Head and Neck Surg 106(4): 345-350).
In addition to standard surgical techniques, laser-based techniques have also been used in nerve repair. However, these methods typically result in heat absorption, which denatures proteins. Thus, there exists in the art a need for improved methods of nerve repair. Improved methods of regenerating nerve fibers, ideally without the formation of scar tissue, would be highly desirable for the treatment of many nerve injuries.